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Review On Thiocyanation PDF
Review On Thiocyanation PDF
Review On Thiocyanation PDF
Abstract
The -thiocyanation of carbonyl compounds is one of the most important processes in
synthetic organic chemistry. These compounds are important precursors for the
production of various biologically important heterocyclic compounds and other
industrially important products. Ammonium thiocyanate (NH4SCN) is a key reagent for
the production of such class of thiocyanate intermediates. In addition to the inherent
efficiency issues, there are also environmental concerns that need to be addressed.
Therefore, in recent years considerable advances have been made for the synthesis of thiocyanation of carbonyl compounds with high selectivity and yield. In this review, we
have summarized various methods for the synthesis of -thiocyanation carbonyl
compounds.
Graphical Abstract
INTRODUCTION
Thiocyanates have gained considerable importance in various areas of organosulfur
chemistry.[1] Thiocyanate is a versatile synthon which can be readily transformed into
other functional groups such as sulfide,[2] aryl nitrile,[3] thiocarbamate,[4] and thionitrile.[5]
The electrophilic thiocyanation of aromatic, hetero aromatic and ketone compounds is a
direct way for carbon sulfur bond formation and is a very useful reaction in organic
synthesis.[6] The thiocyanate function is an interesting part of the molecule, which will be
readily transformed into the other sulfur-bearing functionalities, especially for producing
compounds with pharmaceutical properties.[7] In addition, thiocyanato functionality can
be used as a masked mercapto group or as a precursor for sulfur-containing heterocyclic
compounds, such as thiazolidine and cyclic thioureas.[810]
acyclic ketones. At room temperature and in the absence of catalyst, reaction does not
proceeded efficiently. While the best results were obtained in reflux condition in the
presence of methanol. To optimize the reaction condition, the authors have tested various
oxidants such as Mn(OAc)3.2H2O, Bi(NO3)3.5H2O and IBX, and I2. Only, I2 was found to
be the most effective in terms of conversion and reaction rates. The authors have also
described the proposed reaction mechanism, and according to them the reaction most
likely proceed via the formation of active thiocyanogen, (SCN)2 from I2 and NH4SCN. In
second step the produced (SCN)2 reacts rapidly with the enolizable ketone to produce ketothiocyanate.
were obtained with six-membered rings. The presence of the heteroatom in the sixmembered ring did not affect -thiocyanation.
ketones. The authors have also described the possible reaction mechanism, according to
them reaction follows free radical pathway rather than ionic. In this reaction two moles of
CAN are utilized. The one mole of CAN possibly generate tetralone radical, whereas
second mole converts tetralone radical to tetralone cation via oxidation (Path-I, Scheme
4a). Which on reaction with thiocyanate anion gave desired product. In the second route,
CAN possibly generates first tetralone radical and other mole presumably converts SCN
anion to radical (Path-II, Scheme 4a) to gives desired product.
A mild and environmentally benign synthetic protocol was developed by Lenin and coworkers for chemoselective -thiocyanation of enolizable ketones using ammonium
thiocyanate (NH4SCN) in presence of polystyrene cation exchange resin (Amberlyst-15)
in acetonitrile at room temperature (Scheme 5a-c).[25] Both acetophenones and cyclic
ketones were reacted well to give the -ketothionates in very good yields. The reaction
most likely proceeds via the formation of active thiocyanogen (SCN) from Amberlyst-15
and ammonium thiocyanate. The added advantages of the methodology are high
conversions, mild reaction conditions, ease of the isolation of products and simple
experimental procedure.
Bhaleraoet al. have disclosed an efficient and eco-friendly protocol for -thiocyanation of
ketones and -dicarbonyl compounds using a reagent combination of
bromodimethylsulfonium bromide (BDMS) and ammonium thiocyanate (NH4SCN) in
dichloromethane or acetonitrile at room temperature (Scheme 6a-c).[26] The results of
solvent study exposed that dichloromethane and methanol were also feasible for this
The direct and efficient -thiocyanation of ketones with ammonium thiocyanate has been
achieved by Wu et al. using pyridinium hydrobromide perbromide (PHPB) in acetonitrile
as a solvent at room temperature to produce -ketothiocyanates in excellent yields and
with high selectivity (Scheme 7a-e).[27] Several substituted acetophenones reacted rapidly
with ammonium thiocyanate to afford the corresponding 2-thiocyanatoethanone
derivatives. Thus, this method has wide synthetic utility. Mechanistically, the reaction
may proceed via the electrophilic substitution of acetophenone by (+SCN) intermediately
generated in situ from PHPB and ammonium thiocyanate. Use of PHBP as a versatile,
stable, inexpensive, and commercially available reagent is the major advantage of this
protocol.
Kumar and co-workers have developed an efficient and direct approach for the thiocyanation of ketones with -hydrogens using ammonium thiocyanate as a
thiocyanating agent and oxone as an oxidant in methanol at room temperature (Scheme
Bhalerao et al. have described an efficient and convenient method for -thiocyanation of
ketones and -dicarbonyl compounds utilizing bromodimethylsulfonium bromide
(BDMS) and ammonium thiocyanate (NH4SCN) in acetonitrile to afforded excellent
yield of the products with high selectivity (Scheme 10).[30] In addition, dichloromethane
and methanol were also viable for this transformation; however, in chloroform, brominated product was the major product. Cyclic ketones such as cyclohexanone and
cyclopentanone and corresponding -thiocyanato ketones were obtained in good yields.
In contrast, -substituted -dicarbonyl compounds reacted smoothly to give thiocyanato derivatives. Here, carbonyl compounds firstly underwent bromination
reaction to form -bromo carbonyl compounds, which then rapidly reacted with
ammonium thiocyanate and produce -thiocyanato derivatives. Under the same
conditions, -thiocyanation of benzoylacetone, ethyl acetoacetate, and ethyl
10
A simple and rapid protocol has been developed by WU et al. for the -thiocyanation of
ketones by using ammonium thiocyanate (NH4SCN) and SelectfluorTM as a catalyst. The
reaction was carried out in acetonitrile at room temperature to produce ketothiocyanates in excellent yields and with high selectivity. (Scheme 12a-d).[32] The
reactions were completed smoothly within 25 to 75 min, and the products were isolated
by a simple workup procedure. The SelectfluorTM (1-chloromethyl-4-fluoro-1,4diazoniabicyclo[2,2,2]octanebis(tetrafluoro-borate)) is a commercially available, stable,
11
nonvolatile, nonhygroscopic and easy to handle solid and is more widely used for siteselective fluorination of a variety of carbonyl compounds. Various ketones such as
acetophenones, cyclic ketones, and aliphatic ketones all gave regioselective products in
good to excellent yields. A plausible mechanism for this reaction is proposed by the
authors and according to them, the reaction may proceed via the electrophilic substitution
of ketones by in situ generated thiocyanogen (+SCN) from SelectfluorTM and ammonium
thiocyanate. Compare to other catalysts such as Oxone, Heteropoly acids, FeCl3 and
NBS, the reaction was proceeded efficiently in SelectfluorTM.
Liu and co-workers have reported an efficient protocol for the -thiocyanation of ketones
by utilizing ammonium thiocyanate (NH4SCN) and trichloroisocyanuric acid (TCCA) as
a catalyst in acetonitrile at room temperature, which afforded -ketothiocyanates in
excellent yields and with high selectivity (Scheme 13).[33] No chlorination of
acetophenone was observed under the reaction conditions. Acetonitrile appeared to give
the best results compared to other solvents. Mechanistically, the authors assumed that
TCCA reacts initially with ammonium thiocyanate to generate thiocyanogen (+SCN).
Which was react rapidly with ketones to give the desired -thiocyanatoketone.
An efficient and highly selective protocol for the -thiocyanation of ketones was
developed by Yadav and co-workers anhydrous utilizing ammonium thiocyanate
(NH4SCN) and iron(III) chloride (FeCl3) in dichloromethane at room temperature
(Scheme 14).[34] Only, stoichiometric amount of iron(III) chloride was sufficient to
carried out reaction efficiently. However, no reaction was observed in the absence of
12
catalyst, even under reflux over a long reaction time. The authors have tested various
oxidants, such as (diacetoxyiodo)benzene, manganese(III) acetate, and iron(III) nitrate,
anhydrous iron(III) chlorid were found to be the most effective in terms of conversion.
Various metal triflates such as bismuth(III)-, indium(III)-, samarium(III)-, ytterbium(III)-,
and scandium(III) triflate were also found to be ineffective for this conversion. Both an
electron donating and electron withdrawing substituents on acetophenones reacted readily
with ammonium thiocyanate to provide the corresponding -thiocyanato ketones in good
yields. Similarly, cyclic ketones such as 1-tetralone, 2-phenylchroman-4-one,
cyclopentanone, cyclohexanone, 4,4-dimethylcyclohex-2-enone, 2-methylcyclohexanone,
cycloheptanone and cyclododecanone reacted well under similar conditions to give -oxo
thiocyanates. Furthermore, the sterically hindered acyclic ketone and bulky ketone like
tert-butyl methyl ketone and cyclododecanone respectively afforded the corresponding
thiocyanates in good yields. The best conversions were obtained with cyclohexanone
derivatives. The use of inexpensive and readily available iron(III) chloride makes this
procedure simple, convenient, and practical.
13
CONCLUSION
This review reveals that the development of various convenient methods for the selective
synthesis of -thiocyanato carbonyl compounds in recent years. Many new thiocyanating
reagents have been explored for improving selectivity, purity, and high yield of the thiocyanato carbonyl compounds. Particularly, ammonium thiocyanate (NH4SCN) is
widely used for -thiocyanation of carbonyl compounds efficiently. It should be noted
that though great progress has been achieved in this field over the last few years. This
research area has still further possibilities for growth and with no doubt, we will see an
increasing number of new methods for -thiocyanation of carbonyl compounds.
FUNDING
R. H. V. is thankful to the University Grants Commission for financial assistance [UGCBSR F.7-74/2007 (BSR)].
ACKNOWLEDGMENTS
The authors are thankful to the Department of Chemistry, Gujarat University,
Ahmedabad, for providing the necessary facilities. UGC-Info net and INFLIBNET
Gujarat University are acknowledged for providing the e-source facilities.
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Scheme 1.
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Scheme 2.
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Scheme 3.
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Scheme 4.
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Scheme 5.
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Scheme 6.
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Scheme 7.
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Scheme 8.
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Scheme 9.
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Scheme 10.
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Scheme 11.
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Scheme 12.
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Scheme 13.
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Scheme 14.
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Scheme 15.
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